Over the years, several methods of administering biologically-effective materials to mammals have been proposed. Many medicinal agents are available as water-soluble salts and can be included in pharmaceutical formulations relatively easily. Problems arise when the desired medicinal agent is either insoluble in aqueous fluids or is rapidly degraded in vivo. For example, alkaloids are often especially difficult to solubilize.
One way to solubilize medicinal agents is to include them as part of a soluble prodrug. Prodrugs include chemical derivatives of a biologically-active parent compound which, upon administration, eventually liberate the parent compound in vivo. Prodrugs allow the artisan to modify the onset and/or duration of action of an agent in vivo and can modify the transportation, distribution or solubility of a drug in the body. Furthermore, prodrug formulations often reduce the toxicity and/or otherwise overcome difficulties encountered when administering pharmaceutical preparations. Typical examples of prodrugs include organic phosphates or esters of alcohols or thioalcohols. See Remington's Pharmaceutical Sciences, 16th Ed., A. Osol, Ed. (1980), the disclosure of which is incorporated by reference herein.
Prodrugs are often biologically inert or substantially inactive forms of the parent or active compound. The rate of release of the active drug, i.e. the rate of hydrolysis, is influenced by several factors but especially by the type of bond joining the parent drug to the modifier. Care must be taken to avoid preparing prodrugs which are eliminated through the kidney or reticular endothelial system, etc. before a sufficient amount of hydrolysis of the parent compound occurs. By incorporating a polymer as part of the prodrug system, one can increase the circulating half-life of the drug.
Although the above-mentioned concept of prodrug-based delivery systems has proven to be useful in many instances, there are nonetheless situations where alternatives are desired. For example, Bundgaard in "The Double Prodrug Concept and Its Applications" in Advanced Drug Delivery Reviews, 3 (1989) 39-65, (the contents of which are hereby incorporated by reference) pointed out that in many cases it is difficult to obtain a prodrug which has the proper combination of adequate stability in vitro and high susceptibility to regenerate the parent drug in vivo. As pointed out by Bundgaard, a promising means of overcoming some of the previously encountered shortcomings involves the use of cascade latentiation or "pro-prodrugs". In such systems, the hydrolytic reaction sequence involves a first step which usually is an enzymatic cleavage and the second involves a non-enzymatic hydrolysis that occurs only after the first has taken place. The use of polymeric-based transport systems as part of cascade latentiation technology was not disclosed.
The problems associated with preparing prodrugs of amine-containing drugs was recently highlighted by Shan, D. et al. in "Prodrug Strategies Based on Intramolecular Cyclization Reactions" J. Pharm. Sci. July 1997 Vol.86, No.7, 765-767, (the contents of which are hereby incorporated by reference). To avoid the relative stability of the amide bond, the authors disclose prodrugs which incorporate various moieties which are capable of undergoing intramoleuclar cyclization reactions to release the parent drug. The chemical or biological triggering mechanisms which initiate the cyclization reactions are independent of those which are required for releasing the original drug via hydrolysis of the amide bond. A non-polymeric-containing coumarin-based system is among those disclosed.
Another non-polymeric coumarin-based system is disclosed by Wang, B. et al. in "Chemical Feasibility Studies of a Potential Coumarin-Based Prodrug System" in Bioorganic & Medicinal Chemistry Letters, Vol.6, No.8, pp 945-950, 1996. After esterase catalyzed hydrolysis of the phenolic ester, lactonization and release of the parent compounds was rapid, with t.sub.1/2 being 1.5 to 31 minutes. The technique was also used by the authors to prepare a prodrug of the opioid peptide DADLE. See Bioorganic & Medicinal Chemistry Letters, Vol.6, No.23, pp 2823-2826, 1996. The contents of each of the foregoing are hereby incorporated by reference.
It is believed that in spite of the reported work in the field of double prodrugs, some specific problems were not addressed sufficiently. For example, the previously reported techniques do not sufficiently address the solubility problems of many amine-containing parent compounds. In addition, the problem of designing in variable increases in circulating half-life for the prodrug prior to cyclization and release of the parent compound has also not been addressed. Thus, there continues to be a need to provide additional technologies for forming prodrugs which would benefit from the double prodrug concept. For example, it would be advantageous to provide the artisan with alternative techniques for transport carrier attachment so as to regulate biological effect. Furthermore, it would be desirable to provide additional techniques to address problems associated with involving amino residues and/or hydroxyl residues of parent compounds and thus avoid excessively fast or slow hydrolysis prodrug of the transport form from the parent compound at physiological pH.